PUBLICATION HIGHLIGHTS
NEXT-GEN ALZHEIMER’S MODELLING
Disease modelling is evolving. To bridge the translational gap, research is shifting from traditional 2D cultures to physiologically relevant human iPSC-derived 3D systems. These advanced models offer a more accurate representation of the cellular microenvironment, essential for uncovering complex disease mechanisms. A recent study by Prasannan et al. highlights this advantage. By utilising Human iPSC-derived neural stem cells in a 3D matrix, researchers successfully modelled early Alzheimer’s pathology—specifically insoluble Tau aggregation. This 3D In Vitro Model revealed biochemical features of the disease that standard 2D formats failed to capture.
Study Overview: A New Model for Alzheimer’s Disease
Prasannan et al. introduced a study aimed at better understanding the early pathology of Alzheimer’s disease (AD). The authors argued that existing animal and 2D models often fail to capture the specific evolutionary and spatial mechanisms of human disease, necessitating more physiologically relevant human-based platforms.
Use of Human iPSC-derived Neural Stem Cells
The researchers reported using Human iPSC-derived neural stem cells (hiNSCs) to bypass the need for artificial overexpression of mutations. 1. They explained that cell lines were derived from both healthy individuals (controls) and AD patients carrying specific Presenilin 1 (PSEN1) mutations. 2. They noted that these stem cells were capable of differentiating into various neural cell types, including neurons and astrocytes, directly from patient samples.
Development of 3D Cell Cultures
The study described the creation of a 3D cell culture system designed to mimic the brain’s natural microenvironment. 1. The authors detailed that cells were embedded in an animal-derived matrix, which is rich in extracellular matrix proteins found in the brain. 2. They observed that over a period of 6 to 12 weeks, the cells self-organised into free-floating, ball-like structures. 3. Significantly, the researchers stated that these 3D cultures demonstrated superior neuronal differentiation and maturity compared to traditional 2D flat cultures, evidencing the presence of both glutamatergic and GABAergic neurons.
Advances in Disease Modelling
The authors presented evidence that their 3D system could recapitulate specific biochemical aspects of AD pathology that are difficult to induce in other models. 1. They reported that the AD-derived 3D cultures exhibited significantly higher levels of total Tau and insoluble Tau protein compared to the control groups. 2. The study highlighted the detection of both foetal (3R) and adult (4R) Tau isoforms, suggesting the neurons had reached a level of maturity rarely seen in vitro. 3. The authors concluded that this model effectively reflects early-phase disease features, making it a relevant platform for studying protein aggregation and identifying potential drug targets without the need to force gene overexpression.
References: Prasannan, Preeti et al. “A 3D-induced pluripotent stem cell-derived human neural culture model to study certain molecular and biochemical aspects of Alzheimer’s disease.” In vitro models vol. 1,6 447-462. 14 Nov. 2022, doi:10.1007/s44164-022-00038-5